Yano Seiji, Nokihara Hiroshi, Yamamoto Akihiko, Goto Hisatsugu, Ogawa Hirohisa, Kanematsu Takanori, Miki Toyokazu, Uehara Hisanori, Saijo Yasuo, Nukiwa Toshihiro, Sone Saburo
Department of Internal Medicine and Molecular Therapeutics, University of Tokushima School of Medicine.
Cancer Sci. 2003 Mar;94(3):244-52. doi: 10.1111/j.1349-7006.2003.tb01428.x.
We examined whether interleukin-1 (IL-1), a multifunctional proinflammatory cytokine, progresses or regresses metastasis of lung cancer. Exogenous IL-1beta enhanced expression of various cytokines (IL-6, IL-8, and vascular endothelial growth factor (VEGF)) and intracellular adhesion molecule-1 (ICAM-1) by A549, PC14, RERF-LC-AI, and SBC-3 cells expressing IL-1 receptors. A549 cells transduced with human IL-1beta-gene with the growth-hormone signaling-peptide sequence (A549/IL-1beta) secreted a large amount of IL-1beta protein. Overexpression of IL-1beta resulted in augmentation of expression of the cytokines, ICAM-1, and matrix metalloproteinase-2 (MMP-2). A549/IL-1beta cells intravenously inoculated into severe combined immunodeficiency (SCID) mice distributed to the lung more efficiently and developed lung metastasis much more rapidly than did control A549 cells. Treatment of SCID mice with anti-IL-1beta antibody inhibited formation of lung metastasis by A549/IL-1beta cells. Moreover, A549/IL-1beta cells inoculated in the subcutis grew more rapidly, without necrosis, than did control A549 cells, which produced smaller tumors with central necrosis, suggesting involvement of angiogenesis in addition to enhanced binding in the high metastatic potential of A549/IL-1beta cells. Histological analyses showed that more host-cell infiltration, fewer apoptotic cells, more vascularization, and higher MMP activity were observed in tumors derived from A549/IL-1beta cells, compared with tumors derived from control A549 cells. These findings suggest that IL-1beta facilitates metastasis of lung cancer via promoting multiple events, including adhesion, invasion and angiogenesis.
我们研究了多功能促炎细胞因子白细胞介素-1（IL-1）是否会促进或抑制肺癌转移。外源性IL-1β可增强表达IL-1受体的A549、PC14、RERF-LC-AI和SBC-3细胞中多种细胞因子（IL-6、IL-8和血管内皮生长因子（VEGF））以及细胞间黏附分子-1（ICAM-1）的表达。用带有生长激素信号肽序列的人IL-1β基因转导的A549细胞（A549/IL-1β）分泌大量IL-1β蛋白。IL-1β的过表达导致细胞因子、ICAM-1和基质金属蛋白酶-2（MMP-2）的表达增加。静脉接种到严重联合免疫缺陷（SCID）小鼠体内的A549/IL-1β细胞比对照A549细胞更有效地分布到肺部，且肺转移发展得更快。用抗IL-1β抗体治疗SCID小鼠可抑制A549/IL-1β细胞形成肺转移。此外，皮下接种的A549/IL-1β细胞比对照A549细胞生长更快，且无坏死，对照A549细胞产生的肿瘤较小且有中央坏死，这表明除了增强黏附外，血管生成也参与了A549/IL-1β细胞的高转移潜能。组织学分析表明，与对照A549细胞来源的肿瘤相比，A549/IL-1β细胞来源的肿瘤中观察到更多的宿主细胞浸润、更少的凋亡细胞、更多的血管生成和更高的MMP活性。这些发现表明，IL-1β通过促进包括黏附、侵袭和血管生成在内的多种事件来促进肺癌转移。
